Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes
Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes
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DOI：
10.1016/j.biopsych.2008.03.014
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发表时间：
2008-08-15
影响因子：
10.6
通讯作者：
Chen, Xiangning
中科院分区：
文献类型：
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作者：
Hettema, John M.;An, Seon-Sook;Chen, Xiangning
背景：儿茶酚-C-甲基转移酶 (COMT) 已被研究其在多种精神表型中的可能作用。特别是，一些研究支持该基因与恐慌症和其他焦虑相关特征的关联。方法：我们检查了 COMT 基因与一系列焦虑谱表型的遗传风险的关联。我们使用多元结构方程模型从大量基于人群的双胞胎样本中选择了得分处于神经质、几种焦虑症和重度抑郁症共有的潜在遗传风险因素极端的双胞胎。每对中的一名成员将所得的 589 例病例和 539 名对照受试者样本纳入两阶段关联研究，其中遗传标记在第一阶段进行筛选，其阳性结果在第二阶段进行复制测试。 结果：功能性 val 158met 多态性 (rs4680) 加上选择用于捕获 COMT 基因座主要等位基因变异的其他 9 个单核苷酸多态性标记，分析了病例和对照受试者之间的差异。尽管 rs4680 的 val (G) 等位基因在我们的 I 期和 2 期组合样本中显示出略微显着的关联，但该等位基因与 rs165599 的 A 等位基因的高风险单倍型在病例中显着过高（p = 1.97e-5，优势比 = 1.95）。这种单倍型还预测了神经质的个体差异以及几种焦虑症和重度抑郁症的风险。与之前的研究一致，我们的研究结果是针对女性的。结论：COMT 基因的变异导致一系列焦虑相关表型共有的遗传风险。
Background: Catechol-C-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits.Methods: We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. With one member from each of these pairs, the resulting sample of 589 cases and 539 control subjects were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2.Results: The functional val 158met polymorphism (rs4680) plus nine other single nucleotide polymorphism markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and control subjects. Although the val (G) allele of rs4680 showed marginally significant association in our combined stage I plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p = 1.97e-5, odds ratio = 1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female-specific.Conclusions: Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes.